The present invention concerns heterocyclic carbon compounds comprising spiroisoquinolinone derivatives which have been discovered to be NPY antagonists.
Antagonism of neuropeptide Y receptors has been postulated to reduce food consumption in mammals. Several non-peptidic chemotypes have been disclosed in the literature as being antagonists at the Y1 and at the Y5 subtypes of NPY receptors. (See Gehlert and Hipskind, Exp. Opin. Invest. Drugs, 1997, 6, pp. 1827-1838.)
Neither applicants"" novel spiroisoquinolinone compounds nor the use of these and related spiroisoquinolinones for use in treating medical disorders by means of antagonizing NPY receptors following administration of these compounds is known or suggested by prior art.
Earlier work by our group involved 4-(3-substituted-phenyl)-1,4-dihydropyridine derivatives having NPY antagonist properties. These derivatives conform to structural formula (1). 
In (1) B is either a covalent bond or the group xe2x80x94NHxe2x80x94. The symbol Z denotes hetaryl moieties, examples being piperidine or piperazine.
In U.S. Pat. No. 5,554,621, Z is a fused ring or spiro-fused nitrogen heterocyclic group giving rise to compounds having, for example, a structure such as formula (2). 
Other work by our group has resulted in discovery of certain imidazolone derivatives of formula (3) having NPY antagonism (cf: U.S. Ser. No. 60/079,359). 
As can be seen, these compounds differ significantly in structure from the compounds of the present invention.
The present invention comprises compounds of Formula I, their 
pharmaceutically acceptable acid addition salts and/or their hydrates thereof. In the foregoing structural Formula I, the symbol Z has the following meanings.
Z can be a C9-10alkyl, a C2-6alkenyl group or the moiety Axe2x80x94R, in which A denotes a C1-6 linking alkanediyl or C2-6alkenediyl group connecting R to the piperidino-ring nitrogen atom.
R, in turn, is selected from xe2x80x94OH, xe2x80x94CH(OMe)2, xe2x80x94NR1R2, 1-adamantyl, 
R1 and R2 are independently chosen from hydrogen, C1-4alkyl, or benzyl groups, R3 is selected from hydrogen, C1-4alkyl, C1-4alkoxy, halogen, xe2x80x94NR1, R2, phenyl, phenoxy, and xe2x80x94O2C-phenyl.
In preferred compounds, A is a methylene or ethylene chain and R 
In more preferred compounds, R is 
and in most preferred compounds, R3 is phenyl or phenoxy.
The present invention also pertains to pharmaceutically acceptable salts of the Formula I compounds. Such salts include those derived from organic and inorganic acids such as, without limitation, hydrochloric, hydrobromic, phosphoric, sulfuric, methanesulfonic, acetic, fumaric, tarytaric, moleic, succinic, lactic, citric acid, and the like.
Formula I compounds can be produced by using the general process shown in Scheme 1. The symbol Z is as previously defined. 
The majority of Formula I compounds were synthesized by the route shown in Scheme 1.
For Formula I products wherein Z is 
and A is at least three carbons in length, the synthetic process involves protection of the carbonyl moiety and in most instances straightforward ketal formation accomplishes this objective, as shown in Scheme 2. 
Since structural diversity arises from the variation of Z, Formula II alkylating agents are the focus for synthetic elaboration. Many of the Formula II compounds are either commercially available or amenable to synthetic methods. Scheme 3 illustrates synthesis of Zxe2x80x94X compounds wherein Z is Rxe2x80x94A- and R is, e.g. 
with R3 being phenoxy. 
Another synthetic variation of the Formula I structure can be obtained by operation on a Formula I compound itself. This is illustrated in Scheme 4 where a Suzuki coupling is employed. 
Similar processes employing synthetic modifications familiar to one skilled in the art of synthetic organic chemistry can be utilized to provide additional Formula I compounds. Additional examples and procedures are provided infra in the Specific Embodiments section of the specification.
The compounds of Formula I demonstrate binding affinity at NPY receptors. The binding interaction has been characterized as antagonism at NPY Y5 receptors. This pharmacologic activity was characterized by using BRI-TN-5BI-4 insect cells infected with NPY Y5-recombinant Baculovirus. These cells which express Y5 receptor were used in a radioligand binding assay employing Iodine-125 labeled PYY ligand. The spiroisoquinolones of this invention all showed IC50 values of less than 10 xcexcM, with preferred compounds having IC50 values of less than 500 nM and most preferred compounds having IC50 values of less than 100 nM.
Certain preferred compounds of Formula I were tested in a functional assay where they were found to antagonize NPY-mediated inhibition of forskolin-induced c-AMP accumulation in HEK-293 cells.
Pharmacologically, these compounds act as selective NPY antagonists at NPY Y5 receptor sites. As such, the compounds of Formula I are of value in the treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of neuropeptide Y. Thus, the invention provides methods for the treatment or prevention of a physiological disorder associated with an excess of neuropeptide Y, which method comprises administering to a mammal in need of said treatment an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof. The term xe2x80x9cphysiological disorder associated with an excess of neuropeptide Yxe2x80x9d encompasses those disorders associated with an inappropriate stimulation of neuropeptide Y receptors, regardless of the actual amount of neuropeptide Y present in the locale.
These physiological disorders include:
disorders or diseases pertaining to the heart, blood vessels or the renal system, such as vasospasm, heart failure, shock, cardiac hypertrophy, increased blood pressure, angina, myocardial infarction, sudden cardiac death, congestive heart failure, arrythmia, peripheral vascular disease, and abnormal renal conditions such as impaired flow of fluid, abnormal mass transport, or renal failure;
conditions related to increased sympathetic nerve activity for example, during or after coronary artery surgery, and operations and surgery in the gastrointestinal tract;
cerebral diseases and diseases related to the central nervous system, such as cerebral infarction, neurodegeneration, epilepsy, stroke, and conditions related to stroke, cerebral vasospasm and hemorrhage, depression, anxiety, schizophrenia, dementia, seizure, and epilepsy;
conditions related to pain or nociception;
diseases related to abnormal gastrointestinal motility and secretion, such as different forms of ileus, urinary incontinence, and Crohn""s disease;
abnormal drink and food intake disorders, such as obesity, anorexia, bulemia, and metabolic disorders;
diseases related to sexual dysfunction and reproductive disorders;
conditions or disorders associated with inflammation;
respiratory diseases, such as asthma and conditions related to asthma and bronchoconstriction;
diseases related to abnormal hormone release, such as leutinizing hormone, growth hormone, insulin and prolactin;
sleep disturbance and diabetes;
emesis.
There is evidence that NPY contributes to certain symptoms in these disorders: hypertension, eating disorders, and depression/anxiety; as well as circadian rhythms. Compounds of this invention are expected to be useful in treating these disorders as well as sleep disturbance and diabetes.
Selected compounds are tested further for their ability to block or stimulate NPY-induced feeding in test animals by intraperitoneal administration to the animal prior to inducing feeding behavior with NPY. Taken together, these tests indicate that the compounds of this invention would be useful anorexiants and would function as anti-obesity agents with further use in various clinical eating disorders. Thus, another aspect of the invention concerns a process for reducing food intake in an obese mammal or a mammal with an eating disorder. The process comprises systemic administration to such a mammal of an anorexiant-effective dose of a compound of Formula I or a pharmaceutically acceptable acid addition salt and/or hydrate thereof.
On the basis of pharmacologic testing, an effective dose given parenterally could be expected to be in a range of about 0.05 to 1 mg/kg body weight and if given orally would be expected to be in the range of about 1 to 20 mg/kg body weight.
For clinical applications, however, the dosage and dosage regimen must in each case be carefully adjusted, utilizing sound professional judgment and considering the age, weight and condition of the recipient, the route of administration and the nature and gravity of the illness. Generally, the compounds of the instant invention will be administered in the same manner as for available anorexiant drugs such as Diethylpropion, Mazindol, or Phentermine and the daily oral dose would comprise from about 70 to about 1400 mg, preferably 500 to 1000 mg administered from 1 to 3 times a day. In some instances, a sufficient therapeutic effect can be obtained at lower doses while in others, larger doses will be required.
The term systemic administration as used herein refers to oral, buccal, transdermal, rectal, and parenteral (i.e. intramuscular, intravenous, and subcutaneous) routes. Generally, it will be found that when a compound of the present invention is administered orally, which is the preferred route, a larger quantity of reactive agent is required to produce the same effect as a smaller quantity given parenterally. In accordance with good clinical practice, it is preferred to administer the instant compounds at a concentration level that will produce effective anorectic effects without causing any harmful or untoward side effects. Similarly, the instant compounds can be administered to treat the various diseases, conditions, and disorders listed supra.
Therapeutically, the instant compounds are generally given as pharmaceutical compositions comprised of an effective anorectic amount of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier. Pharmaceutical compositions for effecting such treatment will contain a major or minor amount, e.g. from 95 to 0.5% of at least one compound of the present invention in combination with the pharmaceutical carrier, the carrier comprising one or more solid, semi-solid, or liquid diluent, filler, and formulation adjuvant which is non-toxic, inert and pharmaceutically acceptable. Such pharmaceutical compositions are preferably in dosage unit forms; i.e., physically discrete units containing a predetermined amount of the drug corresponding to a fraction or multiple of the dose which is calculated to produce the desired therapeutic response. The dosage units can contain 1, 2, 3, 4, or more single doses, or, alternatively, one-half, one-third, or one-fourth of a single dose. A single dose preferably contains an amount sufficient to produce the desired therapeutic effect upon administration at one application of one or more dosage units according to the pre-determined dosage regimen usually a whole, half, third, or quarter of the daily dosage administered once, twice, three, or four times a day. Other therapeutic agents can also be present. Pharmaceutical compositions which provide from about 50 to 1000 mg of the active ingredient per unit dose are preferred and are conventionally prepared as tablets, lozenges, capsules, powders, transdermal patches, aqueous or oily suspensions, syrups, elixirs, and aqueous solutions. Preferred oral compositions are in the form of tablets or capsules and may contain conventional excipients such as binding agents (e.g. syrup, acacia, gelatin, sorbitol, tragecanth, or polyvinylpyrrolidone), fillers (e.g. lactose, sugar, maize-starch, calcium phosphate, sorbitol, or glycine), lubricants (e.g. magnesium stearate, talc, polyethylene glycol or silica), disintegrants (e.g. starch) and wetting agents (e.g. sodium lauryl sulfate). Solutions or suspensions of a Formula I compound with conventional pharmaceutical vehicles are generally employed for parenteral compositions such as an aqueous solution for intravenous injection or an oily suspension for intramuscular injection. Such compositions having the desired clarity, stability and adaptability for parenteral use are obtained by dissolving from 0.1% to 10% by weight of the active compound in water or a vehicle consisting of a polyhydric aliphatic alcohol such as glycerine, propyleneglycol, and polyetheleneglycols or mixtures thereof. The polyethyleneglycols consist of a mixture of non-volatile, usually liquid, polyethyleneglycols which are soluble in both water and organic liquids and which have molecular weights from about 200 to 1500.